Latest update on chemokine receptors as therapeutic targets.

Wing Yee Lai,Anja Mueller

doi:10.1042/bst20201114

Abstract

The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand–receptor interactions and the downstream signalling protein–protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.

Highlights

Chemokine signalling was initially identified to be a key coordinator in leukocyte trafficking in immune responses and inflammation [1,2]
The chemokine receptors belong to the class A of G protein-coupled receptor (GPCR) superfamily
To further elucidate the bias towards signalling through β-arrestins for CCL19, a recent finding reveal that the phosphorylation sites at the C-terminus of CCR7 induced by GRKs correlates to the intracellular functions of β-arrestins [36,42,45]

Summary

Introduction

Chemokine signalling was initially identified to be a key coordinator in leukocyte trafficking in immune responses and inflammation [1,2]. This review will summarise recent discoveries regarding biased signalling in the chemokine system and illustrate how the proposed mechanisms potentially transform into the strategies in the discovery and development of targeted therapy. Within the ligand–receptor interactions, it involves dynamic conformational changes in the chemokine ligand with multiple binding sites that facilitates the activation of the receptor [27].

Results

Conclusion